Neuropathic pain (also referred to as neurogenic pain) means pain caused by a disorder or a disease in the peripheral or central somatosensory nervous system and which results from a direct injury, compression or the like to nerve tissue without any noxious stimuli to a nociceptor.
As a therapeutic drug for neuropathic pain, anticonvulsants, antidepressants and antianxiety agents, as well as antiepileptics including pregabalin and gabapentin, which are calcium channel α2δ ligands, have been used (Dooley et al., Trends Pharmacol Sci, 2007, Vol. 28, p. 75). Among these, pregabalin is a world standard therapeutic drug for neuropathic pain, but it is known that administration of pregabalin frequently causes side effects such as dizziness, somnolence, ataxia, weakness and the like, which are thought to be based on the inhibitory effects on the central nervous system (Zaccara et al., Seizure, 2008, Vol. 17, p. 405).
To reduce the dose of pregabalin or gabapentin, combined use of these calcium channel α2δ ligands with various drugs has been studied in recent years. It has been reported that a synergistic analgesic effect can be obtained by combined use of, for example, a calcium channel α2δ ligand with a phosphodiesterase type 5 inhibitor sildenafil, tadalafil or vardenafil (WO 04/016259) or with other drugs (WO 10/025931, WO 09/021058, WO 08/079727, WO 08/079720, WO 07/090661, WO 05/102390, WO 05/025675, WO 01/024792, WO 01/013904, Tomic et al., Eur J Pharmacol, 2010, Vol. 628, p. 75, Park et al., J Korean Med Sci, 2008, Vol. 23, p. 678, Imai et al., Eur J Pharmacol, 2008, Vol. 588, p. 244, Codd et al., Pain, 2008, Vol. 134, p. 254 and Hayashida et al., Anesthesiology, 2007, Vol. 106, p. 1213), or by combined use of gabapentin with a nonopioid analgesic acetaminophen (Hama et al., Neuropharmacology, 2010, Vol. 58, p. 758) or nitro-paracetamol (Curros-Criado et al., Br J Pharmacol, 2009, Vol. 158, p. 601), or with an opioid analgesic oxycodone (Hanna et al., Eur J Pain, 2008, Vol. 12, p. 804) or morphine (De la O-Arciniega et al., Pharmacol Biochem Behav, 2009, Vol. 92, p. 457), or with a vitamin B1 derivative benfotiamine (Mixcoatl-Zecuatl et al., Methods Find Exp Clin Pharmacol, 2008, Vol. 30, p. 431) or vitamin B12 cyanocobalamin (Mixcoatl-Zecuatl et al.). Furthermore, it has been also reported that a synergistic analgesic effect can be obtained by combined use of three drugs, gabapentin, donepezil (cholinesterase inhibitor) and duloxetine (serotonin and noradrenaline reuptake inhibitor) (Hayashida et al., Eur J Pharmacol, 2008, Vol. 598, p. 21).
However, in the combination therapy with a calcium channel α2δ ligand, because such therapy is designed to reduce side effects of the calcium channel α2δ ligand per se, there are instances when an analgesic effect is not sufficiently exhibited due to the reduced dosage of the calcium channel α2δ ligand, and new side effects occur due to the increased dosage of the drug used in combination therewith. For example, in the combined use of gabapentin and morphine, it has been reported that impairment in motor coordination occurs at a dosage sufficient to obtain the synergistic analgesic effect (De la O-Arciniega et al., Pharmacol Biochem Behav, 2009, Vol. 92, p. 457). Therefore, it has been thought that, even in using any other drug in combination therewith, it is difficult to avoid the occurrence of side effects on the central nervous system while obtaining the synergistic analgesic effect.
Accordingly, it could be helpful to provide a therapeutic agent or a prophylactic agent for neuropathic pain, by which a synergistically-enhanced analgesic effect is obtained at a dosage at which a calcium channel α2δ ligand does not produce any side effects as well as which agent does not produce any new side effects on the central nervous system.